Bone marrow transplantation is the treatment of choice for high risk leukemia, aplastic anemia and other immunodeficiency disorders. It is also being used for therapy of other radiation sensitive tumors such as neuroblastoma and for inherited enzyme deficiency disorders. The limiting complication is graft-versus- host disease (GVHD) caused by mature T cells in the donor marrow recognizing histocompatibility differences between donor and host. Studies in animals and humans have shown that removal of mature T cells from the donor marrow while preserving the pluripotent stem cells prevent GVHD. Monoclonal antibodies linked to toxic proteins can specifically kill cells based on cell surface antigen differences. We have developed a panel of T cell selective toxins which kill up to 5 logs of T cells at concentrations non-toxic to human stem cells. We have begun clinical trials of these reagents for 1) prevention of GVHD in MHC matched bone marrow recipients; 2) prevention of GVHD in MHC mismatched BMT. Twenty three patients have now been treated. Ten patients transplanted for high-risk leukemia with major HLA matched sibling marrow are now evaluable. The antibody-ricin conjugate showed no toxicity to the patients. Comparing antibody-toxin treatment with conventional post-transplant methotrexate prophylaxis the hospitalization stay was significantly shorter. Engraftment of donor marrow occurred in all patients and 8 out of 10 showed predominantly donor lymphoid cells 30 days post-transplant. No cases of severe GVHD were observed. Continued clinical trials are underway to increase population size to statistically significant levels to compare GVHD incidence of immunotoxin vs. conventional protocols.